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Bonham, Luke W.; Karch, Celeste M.; Fan, Chun C.; Tan, Chin; Geier, Ethan G.; Wang, Yunpeng; Wen, Natalie; Broce, Iris J.; Li, Yi; Barkovich, Matthew J.; Ferrari, Raffaele; Hardy, John; Momeni, Parastoo; Höglinger, Günter; Müller, Ulrich; Hess, Christopher P.; Sugrue, Leo P.; Dillon, William P.; Schellenberg, Gerard D.; Miller, Bruce L.; Andreassen, Ole A.; Dale, Anders M.; Barkovich, A. James; Yokoyama, Jennifer S.; [...]

CXCR4 involvement in neurodegenerative diseases

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  • Medientyp: E-Artikel
  • Titel: CXCR4 involvement in neurodegenerative diseases
  • Beteiligte: Bonham, Luke W.; Karch, Celeste M.; Fan, Chun C.; Tan, Chin; Geier, Ethan G.; Wang, Yunpeng; Wen, Natalie; Broce, Iris J.; Li, Yi; Barkovich, Matthew J.; Ferrari, Raffaele; Hardy, John; Momeni, Parastoo; Höglinger, Günter; Müller, Ulrich; Hess, Christopher P.; Sugrue, Leo P.; Dillon, William P.; Schellenberg, Gerard D.; Miller, Bruce L.; Andreassen, Ole A.; Dale, Anders M.; Barkovich, A. James; Yokoyama, Jennifer S.; [...]
  • Erschienen: Springer Science and Business Media LLC, 2018
  • Erschienen in: Translational Psychiatry
  • Sprache: Englisch
  • DOI: 10.1038/s41398-017-0049-7
  • ISSN: 2158-3188
  • Schlagwörter: Biological Psychiatry ; Cellular and Molecular Neuroscience ; Psychiatry and Mental health
  • Entstehung:
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total <jats:italic>n</jats:italic> = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson’s disease (PD) and Alzheimer’s disease (AD). In addition to the <jats:italic>MAPT</jats:italic> H1 haplotype, we identified a variant near the chemokine receptor <jats:italic>CXCR4</jats:italic> that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between <jats:italic>CXCR4</jats:italic> and four microglia related genes, namely <jats:italic>CXCL12</jats:italic>, <jats:italic>TLR2, RALB,</jats:italic> and <jats:italic>CCR5</jats:italic>. Evaluating gene expression from post-mortem brain tissue, we found that expression of <jats:italic>CXCR4</jats:italic> and microglial genes functionally related to <jats:italic>CXCR4</jats:italic> was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of <jats:italic>CXCR4</jats:italic> and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond <jats:italic>MAPT</jats:italic>, we show dysregulation of <jats:italic>CXCR4</jats:italic> expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a ‘network’ of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.</jats:p>
  • Zugangsstatus: Freier Zugang